Medical care of heart failure (HF) has been stagnant for the past 20 years; innovative therapy is urgently needed. A novel therapeutic target, mitochondrial dysfunction, has been implicated in multiple diseases, including heart failure. However, there currently is no specific treatment for mitochondrial dysfunction in human heart failure or any other disease. Mitochondria-based therapy development has been hampered both by limited understanding of how mitochondrial impairment causes cardiac dysfunction, and by a lack of interventions shown to improve mitochondrial function. Recently, we demonstrated in a murine model, that impaired mitochondrial oxidative phosphorylation led to an increased myocardial NADH/NAD+ ratio and increased mitochondrial protein acetylation, without affecting mitochondrial ROS production or ATP synthesis. These changes rendered the heart susceptible to chronic stresses, which accelerated the development of heart failure. We observed a similar increase of NADH/NAD+ ratio and increase in protein acetylation in animal models of heart failure due to chronic pressure overload with no prior mitochondrial dysfunction. Supplying the NAD+ precursor, nicotinamide mononucleotide (NMN), to these mice normalized the NADH/NAD+ ratio, prevented increased mitochondrial protein acetylation and improved cardiac function. Though NMN is not orally bioavailable, we and others have shown that oral supplementation with nicotinamide riboside (NR), the precursor from which NMN is produced, also decreases (normalizes) tissue NADH/NAD+ ratio and improves mitochondrial function in mouse models. These animal model results suggest a conceptually innovative mechanism linking mitochondrial dysfunction to the development and progression of heart failure that is distinct from the existing hypotheses of oxidative stress and energy starvation. Thus, we hypothesize that oral supplementation with NR will improve the NADH/NAD+ ratio caused by mitochondrial dysfunction during chronic stresses, and improve functional capacity and ventricular function in systolic heart failure. We therefore propose a first-in-human, safety and tolerability trial of the nutritional supplement, nicotinamide riboside (NR) in 30 participants wit clinically-stable, systolic heart failure. NR is a relative of niacin, but a closer relative of nicotinamide which, unlike niacin, does not induce flushing or pruritis and has no effect on lipid levels. NR does not induce insulin resistance or dysglycemia in mouse models. Thus, NR would potentially be cheap, safe, well-tolerated and readily available. The application is in response to the program announcement of Nutrition and Diet in the Causation, Prevention, and Management of Heart Failure as NR has recently been approved for human use as a health supplement. As NR has not been used therapeutically in heart failure patients, we will utilize the R21 mechanism to support a pilot study with the following aims: 1) to determine the safety and tolerability of NR in patients with clinically-stable, systolic heart failure (LVEF <40%); 2) to determine whether, at the doses employed, NR has measureable effects on leukocyte NAD+ level and NADH/NAD+ ratio; and 3) to explore the potential range of effects of NR supplementation on heart failure surrogate endpoints.